Ketorolac tromethamine has the following structure: ##STR1##
Ketorolac tromethamine is useful as an analgesic and anti-inflammatory agent. There exist a number of prior art methods for the production of amine salts of ketorolac, see, for example, U.S. Pat. Nos. 4,347,185 and 4,089,969. Typically these salts are prepared by solubilizing ketorolac acid and tromethamine in a nonpolar organic solvent and isolating the resulting tromethamine salt. However, these procedures rely on the low solubility of tromethamine in most nonpolar organic solvents, and results in inconsistent yields, incomplete salt formation, low potency, and inconsistent and unacceptable bulk densities of the final product.
For example, in U.S. Pat. No. 4,089,969, is disclosed a process for preparing amine salt derivatives of ketorolac acid wherein the process is conducted in a single or binary solvent system, i.e., in water, alone or in combination with an inert, water-miscible organic solvent. Exemplified is a process for preparing an amine salt of ketorolac acid where in the organic solvent utilized is benzene. However, benzene has the problem of being a carcinogen and therefore undesirable for use in preparing in a pharmaceutical product.
Alternate approaches have substituted acetonitrile as the reaction solvent and resulted in a product having good yields and high purity; however, like benzene, acetonitrile must be controlled at extremely low levels in the final product.
Further, such processes of the prior art yield lots of final product with inconsistent and unacceptable bulk densities. Bulk density is of great importance in preparing pharmaceutical products for oral administration, for example, when one considers the size of a high-dose capsule or the homogeniety of a low-dose formulation in which there are large differences in drug and excipient bulk densities. In addition, for the manufacture of solid dosage forms, it is desirable to have the bulk density in the range of about 0.3 to about 0.7 g/mL, or more preferrably about 0.35 to about 0.5 g/mL. The solid product obtained by such single or binary solvent distillation methods yields such product with such varied degree of bulk density that is not suitable or useful for oral formulations.
Thus there continues to be a need for improved methods for producing ketorolac tromethamine which provide a product of high quality and potency while avoiding undesirable solvents, and also yields a product of suitable bulk density for oral formulations.